Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants

Nutrients. 2021 Nov 30;13(12):4336. doi: 10.3390/nu13124336.


Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named "HAMLET," (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET's possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET's discovery, formation and bioactive benefits will be reviewed.

Keywords: HAMLET; NF-κB pathway; bioactive proteins; cytotoxicity; human milk; inflammation; necrotizing enterocolitis; pasteurization.

Publication types

  • Review

MeSH terms

  • Caseins / chemistry
  • Cytotoxins / toxicity*
  • Diet / adverse effects
  • Food Handling*
  • Food Storage
  • Humans
  • Infant, Newborn
  • Infant, Premature*
  • Lactalbumin / toxicity*
  • Milk, Human / chemistry*
  • Oleic Acids / toxicity*


  • Caseins
  • Cytotoxins
  • HAMLET complex, human
  • Oleic Acids
  • Lactalbumin